Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood and adolescence. Using contemporary multimodal therapies, more than 75% of patients with localized RMS are cured However, patients with recurrent disease experience 5-year survival rates of only 30%, and this outcome has not significantly improved in more than 20 years. Over the past 6 years, comprehensive genomic, epigenomic, proteomic, and drug-sensitivity profiling of RMS has been completed and integrated into a central database (iRDb). In addition, a multidisciplinary RMS translational research team (RMS-TRT) has been assembled to use the iRDb to identify tumor vulnerabilities that can be exploited therapeutically. Three signaling pathways have been identified that appear to be vulnerable to novel molecular-targeted regimens, which have shown promise in laboratory studies. In this proposal, comprehensive preclinical testing of those regimens (e.g., pharmacokinetics, pharmacodynamics, imaging and efficacy studies) will be performed to determine the most effective treatment. The results from these studies will be used to design the next RMS clinical trial at St. Jude Children's Research Hospital. Therefore, the successful completion of the Aims presented here will directly affect human health. One unique and innovative aspect of this proposal is the Childhood Solid Tumor Network (CSTN), a website (http://www.stjude.org/CSTN/) through which all of the iRDb data are shared freely with the international biomedical research community with no obligation to collaborate. The majority (>95%) of the data available through the CSTN is unpublished, but all of it is shared to accelerate discovery and advance cures for pediatric cancer. To date, 314 requests from 122 investigators at 46 institutions across 11 countries have been fulfilled. I have a proven record of moving basic science discoveries into clinical trials and then sharing findings with the national and international research communities to affect the greatest change in global human health. No other center has the team, resources, expertise, or tools available to perform the studies presented here and efficiently move the most promising findings directly into a clinical trial.